Our understanding of selective vulnerability continues to be hampered by our lack of data that place implicated molecules, such as glutamate receptors (GluRs), in the context of the neural circuits that are prone to age-related functional compromise or degeneration. Our major goal will be to establish precise linkage between specific GluRs and key corticocortical and hipoocampal circuits. We will also define age-related and lesion- induced changes in the distribution of GluRs with a high level of subunit and circuit specificity. Such analyses will both clarify receptor diversity of excitatory circuits, and reveal the GluR profile that is related to vulnerability in normal aging and Alzheimer's Disease. There are four components: 1) Production of necessary reagents. Our program to produce and characterize subunit specific monoclonal antibodies (mAb) to GluRs will continue, with the highest priority being the development of mAbs that distinguish all AMPA and kainate subunits (i.e., GluR1-7, and KA1,2), and subunits NMDAR2 A-D. II) Receptor coding of excitatory circuits. We have hypothesized that convergent excitatory circuits will exhibit specificity in their GluR profile, and the GluR profile will be directly related to both the functional role and relative vulnerability of a given circuit. The specificity in GluR profile will be apparent primarily at the level of individual dendritic segments, spines, and synapses that can be equated with identified incoming afferents. To test this, GluR distribution in hippocampus and visual cortex will be characterized at high resolution with increased subunit specificity , and in the context of identified circuits that very both in their functional attributes and vulnerability to degeneration. III) Effects of Aging. We have hypothesized that age-related impairments may be mediated by subtle shifts in specific GluR subunits in otherwise structurally intact circuits. We have described an NMDA specific alteration in the dendritic segments subserving the perforant path input to the dentate gyrus that occurs in aged primates. We will pursue this finding with subunit specific antibodies and high resolution neuroanatomic techniques to determine its specificity and degree to which it occurs without structural damage to the circuit. IV) Circuit-specific shifts in GluRs following disruption. We have hypothesized that deafferentation by destruction of the perforant path will also cause changes in GluRs in the dentate gyrus, but these changes will be multi-faceted structural and molecular changes reminiscent of AD. In contrast, functional deafferentation might cause GluR changes more reminiscent of normal aging. ERC in young and aged monkeys and rats will be lesioned either electrolytically or functionally disconnected from the dentate gyrus with TTX injections to test this hypothesis. The lesion- induced changes in GluR expression will be analyzed with respect to time course of effects, family and subunit specificity, relative contribution of molecular vs structural postsynaptic responses, and dependence of the effect on age.